Thrombosis and thromboembolism which is a complication of thrombosis (hereinafter referred to as thromboembolic disease) are ranked high along with cancer as the cause of death of adults, and have become important problems in recent years. Thromboembolic disease occurs by the formation of a thrombus at a site of vascular injury. Alternatively, thromboembolic disease occurs when a thrombus is released and is carried by the blood stream into another blood vessel where the thrombus obstructs a blood vessel at another site. Thromboembolic disease includes, for example, venous thromboembolism which is a collective term for deep venous thrombosis and pulmonary embolism, cerebral stroke, angina pectoris, myocardial infarction, other various arterial and venous thrombosis and the like.
Tissue factor expressed on a vascular wall due to the injury of a blood vessel and the like becomes the starting point of the blood coagulation cascade and forms a complex with blood coagulation factor VII which is present in blood in a very small quantity. This complex activates blood coagulation factor IX and blood coagulation factor X, and activated blood coagulation factor X converts prothrombin to thrombin. Thrombin converts fibrinogen to fibrin and finally insoluble fibrin is formed (the initial stage). It is supposed that thrombin produced in the process promotes the formation of a thrombus at the initial stage and is important for hemostasis. On the other hand, it has been reported that thrombin activates blood coagulation factor XI and causes explosive thrombin production via activated blood coagulation factor XI (hereinafter also referred to as FXIa) (the amplification stage), which results in an increase in thrombi (see Non Patent Literatures 1 to 3).
For the treatment and/or prevention of thromboembolic disease, anticoagulant agents are generally used. Though conventional anticoagulant agents exhibit excellent antithrombotic actions, bleeding complications, which are serious side effects, have been problematic. Alternatively, in order not to cause bleeding complications, the doses of the agents are limited and it is supposed that there is a possibility that the agents do not exhibit sufficient antithrombotic actions. Under such conditions, an agent for treating and/or preventing thrombosis and thromboembolism having a novel mechanism of action, which suppresses the growth of or increase in pathological thrombi and does not affect the formation of hemostatic thrombi, is required. As one of the targets of the agent, FXIa is attracting attention in recent years. Blood coagulation factor XI is one of plasma serine proteases which are involved in the regulation of blood coagulation and becomes FXIa by activated blood coagulation factor XII, thrombin or itself. FXIa is one of constituents of the blood coagulation pathway which is referred to as the intrinsic system or the contact system in the classical blood coagulation cascade and activates blood coagulation factor IX by selectively cleaving peptide bonds of Arg-Ala and Arg-Val. The safety of FXIa is supported by the observations that the blood coagulation factor XI deficiency in humans, which is called hemophilia C, results in mild to moderate bleeding characterized primarily by postoperative or posttraumatic hemorrhage. In addition, the effects and the high safety of FXIa are demonstrated by the experimental results of experimental thrombosis and bleeding models which used blood coagulation factor XI deficient mice and the experimental results of an anti-blood coagulation factor XI neutralizing antibody or an antisense in experimental thrombosis and bleeding models which used monkeys or rabbits, in addition to the results of observations of the blood coagulation factor XI deficiency in humans (see Non Patent Literatures 4 to 8).
Based on the above results, it is expected that FXIa is a very attractive target without exhibiting the side effect of bleeding when developing an antithrombotic agent for treatment and/or prevention and an FXIa inhibitor becomes a very potent and safe antithrombotic agent for treatment or prevention without having any undesirable side effects such as bleeding.
Incidentally, as compounds of prior arts to the present invention, the following compounds are described:
It has been described in Patent Literature 1 that a compound represented by general formula (A):
(wherein, AA represents a 5- to 12-membered heterocycle or the like; L1A represents —CH═CH— or the like; R11A represents benzyl or the like; and MA represents imidazolyl or the like) is useful as a selective inhibitor of FXIa or a dual inhibitor of FXIa and plasma kallikrein.
In addition, it has been described in Patent Literature 2 that a compound represented by general formula (B-I):
(wherein, AB represents a 5- to 12-membered heterocycle or the like; L1B represents —CH═CH— or the like; R11B represents benzyl or the like; R3A represents phenyl or the like; R4B represents chlorine or the like; R8aB represents hydrogen or the like); or general formula (B-II):
(wherein, MB represents pyridyl or the like; and the other symbols have the same meanings as described above) inhibits FXIa and/or plasma kallikrein.
Further, it has been described in Patent Literature 3 that a compound represented by general formula (C):
(wherein, WC represents CO or the like; GC represents a direct bond or the like; G1C, G2C, G3C and G4C each independently represent C or N or the like; R9C represents an aryl or the like; R10C represents a heteroaryl or the like; and R1AC represents a heteroarylalkyl or the like) is useful as a γ secretase modulator. However, it is not reported that the compound represented by formula (C) has an FXIa inhibitory activity.
Furthermore, it has been described in Patent Literature 4 that a compound represented by general formula (D):
(wherein, R1D represents hydrogen or the like; R2D represents an aryl or the like; R3D represents hydrogen or the like; R4D represents hydrogen or the like; and R5D represents a heteroarylalkyl or the like) is useful as a p38 MAP kinase modulator.
In addition, it has been described in Patent Literature 5 that a compound represented by general formula (E):
(wherein, LE represents a linker providing 0 to 6 atoms or the like; XE represents a heteroaryl or the like; ZE represents a halogen or the like; QE represents CO or the like; and R2E and R3E each independently represent hydrogen, an aryl or the like) is useful as a dipeptidyl peptidase inhibitor.
Further, it has been described in Patent Literature 6 that a compound represented by general formula (F):
(wherein, Cyc1F represents a 5- to 10-membered heteroaryl or the like, Cyc2F represents a C5-C10 aryl or the like, Cyc3F represents a C5-C10 aryl or a 5- to 10-membered heteroaryl or the like, U represents CH2 or the like, Y represents N or C(R5F) or the like, and R6F represents a 5- to 10-membered heteroaryl or the like) is useful as a selective inhibitor of FXIa or a dual inhibitor of FXIa and plasma kallikrein.
However, none of literature specifically discloses the compound of the present invention.